Rhodium- and platinum-catalyzed [4+3] cycloaddition with concomitant indole annulation: Synthesis of cyclohepta[b]indoles

Article abstract of DOI:10.1002/anie.201209266

Various substituted cyclohepta[b]indoles were prepared from propargylic ethers and dienes by a tandem indole annulation/[4+3] cycloaddition (see scheme; Boc=tert-butoxycarbonyl). Both acyclic and cyclic dienes participated in the [4+3] cycloaddition to af

Full text of DOI:10.1002/anie.201209266

Angewandte
Chemie
DOI: 10.1002/anie.201209266
Heterocycles
Rhodium- and Platinum-Catalyzed [4+3] Cycloaddition with
Concomitant Indole Annulation: Synthesis of Cyclohepta[b]indoles**
Dongxu Shu, Wangze Song, Xiaoxun Li, and Weiping Tang*
Seven-membered rings fused with an indole, cyclohepta[b]-
indoles, are present in many bioactive natural products such
as silicine,[1] ervitsine,[2] and actinophyllic acid (Figure 1).[3]
Scheme 1. [4+3] Cycloaddition of vinyl carbenes and dienes.
Figure 1. Representative cyclohepta[b]indoles.
was recently reported that vinyl metal carbenes could be
conveniently generated from propargylic ethers tethered with
a nucleophile for a [3+2] cycloaddition[14] and a synthesis of
furans.[15] We envisioned that the vinyl metal carbene 2,
derived from 1, would undergo a formal [4+3] cycloaddi-
tion[16] with diene 3 to afford the cyclohepta[b]indole 4 by
either a cyclopropanation/Cope rearrangement sequence
involving the divinyl-cyclopropane 5, or an unusual [4+4]
cycloaddition to form the eight-membered metallacycle 6
with subsequent reductive elimination. Both indole and
seven-membered rings may be constructed very efficiently
in this tandem process from simple building blocks.
The transformation from the propargylic ether 1 to the
product 4 requires a metal catalyst which has enough
p acidity[17] to induce cyclization of 1, thus forming a carbene
intermediate, and the ability to promote cycloadditions. The
catalyst [{Rh(CO)2Cl}2] can facilitate 1,3-acyloxy migration of
propargylic esters, a process that is typically catalyzed by p-
acidic metals,[17] and effects cycloadditions as well.[18,19] When
a mixture of the propargylic ether 1a and diene 3a was
treated with this catalyst at 808C, no reaction occurred
(Table 1, entry 1). We have previously found that electron-
deficient phosphine or phosphite ligands often increase the
acidity of rhodium catalysts and promote 1,2-acyloxy[20] or 1,3-
acyloxy[19] migration of propargylic esters. Indeed, a mixture
of the [4+3] cycloaddition product 4a and simple indole 7 was
observed when 1a was treated with [{Rh(CO)2Cl}2] in the
presence of such ligands (entries 2–4). The amount of 7 could
be minimized by employing a greater excess of 3a (entry 4). A
67% yield of the isolated tricyclic product 4a could be
obtained in the presence of a rhodium(I) metal complex and
an electron-deficient phosphite ligand.
They are also important structural motifs in numerous
pharmaceuticals with various pharmacological properties
such as inhibition of deacetylase SIRT1,[4] inhibition of
adipocyte fatty-acid-binding protein (A-FABP),[5] and anti-
tubercular activity.[6] Most previous efforts have focused on
building the seven-membered ring and the indole separately
by cyclization reactions.[4,5,7] Recently, an elegant three-
component [4+3] cycloaddition was reported by Wu and co-
workers for the synthesis of cyclohepta[b]indoles from
indoles, aldehydes, and dienes.[8] It represents the first
example of a [4+3] cycloaddition involving an indole as the
2p component. We herein report an efficient and versatile
process that allows the simultaneous construction of both the
indole and seven-membered ring through a [4+3] cyclo-
addition with concomitant indole annulation.[9]
Vinyl metal carbenes derived from vinyl diazo compounds
can undergo formal [4+3] cycloadditions with dienes through
a
cyclopropanation/Cope
rearrangement
sequence
(Scheme 1).[10,11] Similarly, vinyl Fisher carbenes[12] or vinyl
gold carbenes derived from propargylic esters[13] can also
react with dienes to form various seven-membered rings. It
[*] D. Shu, W. Song, X. Li, Prof. Dr. W. Tang
The School of Pharmacy, University of Wisconsin
Madison, WI 53705-2222 (USA)
E-mail: wtang@pharmacy.wisc.edu
D. Shu
Department of Chemistry, University of Wisconsin
[**] We thank theNIH (R01 GM088285) for funding. W.T. is grateful for
a Young Investigator Award from Amgen.
We also examined PtCl2, PtCl2/alkene, and PtCl2/PPh3, all
of which have been used in the generation of vinyl platinum
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201209266.
Angew. Chem. Int. Ed. 2013, 52, 3237 –3240
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3237

.
Angewandte
Communications
Table 1: Optimization for the reaction between 1a and 3a.[a]
Table 2: Scope of propargylic ethers and acyclic dienes.[a]
Entry
1
3
Product
Yield
[%]
Entry
Conditions
4a
4a/7
Yield [%][b]
1[b]
2[b]
1a (X=OMe)
1b (X=OBn)
3a
3a
8a
8a
82
80
1[c]
2[c]
3[c]
4
5
6
7
8
9
10
11
12
13
14
[{Rh(CO)2Cl}2]
no reaction
35
–
[{Rh(CO)2Cl}2], P[(CF3)2C6H3]3
[{Rh(CO)2Cl}2], P(C6F5)3
[{Rh(CO)2Cl}2], P[OCH(CF3)2]3
PtCl2
PtCl2, octene
[Pt(PPh3)2Cl2]
PtCl2, CO (1 atm)
PtCl2, P[OCH(CF3)2]3
PtCl2, P[(CF3)2C6H3]3
PtCl2, P(C6F5)3
[IrCl(CO)(PPh3)2]
PdCl2
1:1
2:1
4:1
1.6:1
2:1
–
4:1
8:1
10:1
>20:1
–
53
70 (67)[d]
28
21
no reaction
18
66
3
4
5
6
1c (R=CO2Et)
1d (R=OMe)
1e (R=CH2OH) 3a
3a
3a
4c
4d
4e
4 f
83
86
52
83
31
85[d]
1 f (R=CHO)
3a
no reaction
no reaction
no reaction
–
–
[AuClP(p-CF3C6H4)3]
[a] Reaction conditions: 10 mol% metal catalyst, 20 mol% ligand, diene
3a (5 equiv), 808C, 1,4-dioxane, Na2CO3, 12 h, unless noted otherwise.
[b] Yields based on 1H NMR spectroscopy. [c] Used 2 equiv of 3a.
[d] Yield of isolated product. Boc=tert-butoxycarbonyl, TIPS=triiso-
propylsilyl.
7[c]
1g
3a
4g
56
carbenes from propargylic ethers.[14,15] A low yield of 4a or no
product, however, was observed using these catalysts
(Table 1, entries 5–8). We suspect that the coordination of
the bidentate diene 3a to PtCl2 may reduce the acidity of the
metal. Electron-deficient phosphite or phosphine ligands
were then added to further enhance the reactivity of the PtCl2
catalyst (entries 9–11). Indeed, the yield of 4a was increased
significantly. The tris(pentafluorophenyl)phosphine ligand
provided the highest yield of the isolated product 4a
(entry 11). A lower catalyst loading led to lower conversion,
and other metal catalysts did not afford the desired product
(entries 12–14).
With the two catalysts in hand (Table 1, entries 4 and 11),
we studied the scope of this tandem indole annulation/[4+3]
cycloaddition with different propargylic ethers (Table 2,
entries 1–7). The ketone 8a was isolated in 82% yield after
in situ hydrolysis of the silyl enol ether 4a (entry 1). A benzyl
ether could also be tolerated (entry 2), and other leaving
groups (e.g. X = OH, OPiv, or Cl) led to a complex mixture.
Electron-withdrawing or electron-donating groups on the
benzene ring change the nucleophilicity of the aniline nitro-
gen atom, however the efficiency of the indole annulation/
[4+3] cycloaddition did not change with either type of
substituent (entries 3 and 4). A lower yield was observed for
the substrate 1e having a free alcohol (entry 5), and a formyl
group did not interfere with the tandem reaction (entry 6).
The secondary propargylic ether 1g also participated in the
tandem reaction and yielded 4g (entry 7).
8
1a
3b
3c
3d
3d
4ab
8ac
4ad
4gd
90
59
66
9[b,d] 1a
10[d] 1a
11
1g
50
(d.r.=3:1)
[a] Reaction conditions: PtCl2 (10 mol%), P(C6F5)3 (20 mol%), diene 3
(5.0 equiv), 808C, 1,4-dioxane, Na2CO3, 12 h. Yields are those of the
isolated products. [b] The resulting product was treated with aqueous HCl
(4m). [c] Used 1.5 equiv of3a. [d] [{Rh(CO)2Cl}2] (5 mol%) and P[OCH-
(CF3)2]3 (20 mol%) were employed. TBS=tert-butyldimethylsilyl.
We next investigated the scope of acyclic dienes that could
be used in this process (Table 2, entries 8–10). The more
functionalized 2,3-disubstituted diene 3b afforded 4ab in high
yield (entry 8, Table 2). The monosubstituted diene 3c
produced 8ac in 59% yield in the presence of a rhodium
catalyst (entry 9), and lower yields were obtained when
various platinum catalysts were employed in this case. The
same trend was also observed for 3d (entry 10). When
3238
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3237 –3240

Angewandte
Chemie
Table 3: Scope of cyclic dienes for the tandem reaction with the
propargylic ether 1a.[a]
platinum catalysts were employed, the yield of 4ad was 20–
30% lower than that obtained from using the rhodium
catalyst, and a diastereomeric mixture of 4gd was isolated
when 3d was reacted with the propargylic ether 1g (entry 11).
A complex mixture was observed when substrate 1a was
treated with 2-methyl-1,3-butadiene in the presence of either
the platinum or rhodium catalyst, thus suggesting that the
siloxy substituent is critical for the reactivity of acyclic dienes.
We were pleased to find that the furan 9a participated in
the tandem reaction and afforded the tetracyclic product 10a
in 71% yield (Table 3, entry 1). The arylation product 11a
was isolated in 14% yield. For the 3,4-disubstituted furan 9b,
a single product, 10b, was observed (entry 2). The yields for
the ester-substituted furans 9c and 9d were slightly lower
(entries 3 and 4), and two tetracyclic isomers were obtained
for the nonsymmetric furans 9d and 9e (entries 4 and 5). The
2,3-dimethylfuran 9 f only afforded one tetracyclic isomer
(10 f; entry 6), however, the arylation product 11 f was also
obtained in this case. When pyrrole was employed, only the
arylation product was observed.[21] To our surprise, the
tetracyclic product 10g could be prepared in 63% yield
from the simple cyclopentadiene (9g; entry 7). Cyclohexa-
diene (9h) also participated in the tandem reaction and
afforded the free indole 10h after removing the Boc-protect-
ing group (entry 8). It is worth mentioning that the substitu-
tion pattern of the products and the scope of dienes are
complementary to that of the [4+3] cycloaddition for the
synthesis of cyclohepta[b]indoles reported by Wu and co-
workers[8]
Entry
9
Products[b]
1[c]
9a
10a (71%)
11a (14%)
2
3
9b
9c
10b (79%)
10c (52%)
4
5
9d
10d (44%)
10d’ (23%)
Possible mechanisms for the tandem indole annulation/
[4+3] cycloaddition are shown in Scheme 2. The metal
carbene 14 can be generated by 5-endo-cyclization and
elimination of methanol.[14,15] Several potential pathways
can be proposed for the cycloaddition. In path a, cyclo-
propanation of diene 3a may afford the divinylcyclopropanes
15 or 16, which undergo Cope rearrangement to produce the
products 4a or 4a’, respectively. In path b, nucleophilic attack
9e
10e (83%)[d]
10e’
10e /10e’=1:1.5
6
9 f
10 f (58%)
11 f (30%)
7
8
9g
9h
10g (63%)
10h (61%)[e]
[a] Reaction conditions: PtCl2 (10 mol%), P(C6F5)3 (20 mol%), diene 5
(1.5–5.0 equiv), 808C, 1,4-dioxane, Na2CO3, 12 h. [b] Yield for isolated
product given within parentheses. [c] PtCl2 (5 mol%), P(C6F5)3
(10 mol%) [d] Yield for 10e and 10e’ combined. [e] The Boc protecting
group was removed by the treatment with trifluoroacetic acid. The yield is
the overall yield for two steps.
of the silyl enol ether onto the vinyl carbene may produce the
ionic intermediate 17. The metallacycle 18 can be formed
through path b1 directly or from a six-membered metallacycle
by path b2 followed by a 1,3-shift. Reductive elimination of
Scheme 2. Proposed mechanisms for the [4+3] cycloaddition accom-
panied by an indole annulation.
Angew. Chem. Int. Ed. 2013, 52, 3237 –3240
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3239

.
Angewandte
Communications
Wood, Org. Lett. 2009, 11, 4532; e) M. Amat, N. Llor, B. Checa,
E. Molins, J. Bosch, J. Org. Chem. 2010, 75, 178; f) C. L. Martin,
L. E. Overman, J. M. Rohde, J. Am. Chem. Soc. 2010, 132, 4894;
g) H. Zaimoku, T. Taniguchi, H. Ishibashi, Org. Lett. 2012, 14,
1656.
18 can then afford the product 4a. Alternatively, cyclization
through path b3 may produce product 4a directly. In path c1,
a concerted [4+4] cycloaddition between the carbene 14 and
diene 3a may also lead to metallacycle 18. A [4+3] cyclo-
addition with a concomitant elimination of the metal through
path c2 is also possible and may yield product 4a directly.
Based on the regioselectivity reported previously,[10,11]
cyclopropanation of diene 3a should occur on the electron-
rich silyl enol ether selectively and afford the cyclopropane
16, which would produce the isomeric product 4a’. Since only
isomer 4a was observed, [4+3] cycloadditions through paths b
or c are more likely for the dienes 3 and 9. This reactivity
represents a new class of [4+3] cycloadditions in which the
2p component is an indole derivative.[8]
[8] X. Han, H. Li, R. P. Hughes, J. Wu, Angew. Chem. 2012, 124,
10536; Angew. Chem. Int. Ed. 2012, 51, 10390.
[9] For recent reviews on indole synthesis, see: a) J. Barluenga, F.
Rodriguez, F. J. Fananas, Chem. Asian J. 2009, 4, 1036; b) D. F.
Taber, P. K. Tirunahari, Tetrahedron 2011, 67, 7195; c) R.
Vicente, Org. Biomol. Chem. 2011, 9, 6469.
[10] For reviews on sequential cyclopropanation and Cope rear-
rangement, see: a) H. M. L. Davies, Tetrahedron 1993, 49, 5203;
b) H. M. L. Davies, J. R. Denton, Chem. Soc. Rev. 2009, 38, 3061.
[11] For selected examples of sequential cyclopropanation and Cope
rearrangement, see: a) H. M. L. Davies, H. D. Smith, O. Korkor,
Tetrahedron Lett. 1987, 28, 1853; b) H. M. L. Davies, M. J.
McAfee, C. E. M. Oldenburg, J. Org. Chem. 1989, 54, 930;
c) R. P. Reddy, H. M. L. Davies, J. Am. Chem. Soc. 2007, 129,
10312; d) J. P. Olson, H. M. L. Davies, Org. Lett. 2008, 10, 573.
[12] a) W. D. Wulff, D. C. Yang, C. K. Murray, J. Am. Chem. Soc.
1988, 110, 2653; b) J. Barluenga, F. Aznar, A. Martin, S.
Garciagranda, M. A. Salvado, P. Pertierra, J. Chem. Soc. Chem.
Commun. 1993, 319; c) J. Barluenga, F. Aznar, A. Martin, J. T.
Vazquez, J. Am. Chem. Soc. 1995, 117, 9419; d) J. Barluenga, F.
Aznar, M. Fernandez, Chem. Eur. J. 1997, 3, 1629; e) M.
Hoffmann, M. Buchert, H. U. Reissig, Chem. Eur. J. 1999, 5,
876; f) J. Barluenga, J. Alonso, F. Rodriguez, F. J. Fananas,
Angew. Chem. 2000, 112, 2555; Angew. Chem. Int. Ed. 2000, 39,
2459; g) J. Barluenga, J. Alonso, F. J. Fananas, Chem. Eur. J.
2005, 11, 4995; h) F. Aznar, M. Fananas-Mastral, J. Alonso, F. J.
Fananas, Chem. Eur. J. 2008, 14, 325.
Treatment of the product 4ab with HF/pyridine provided
19, which could be easily functionalized [Eq. (1)]. Saegusa
oxidation[22] of the same silyl enol ether yielded enone 20.
In summary, a novel indole annulation/[4+3] cycloaddi-
tion sequence was developed for the synthesis of various
substituted cyclohepta[b]indoles. Both acyclic and cyclic
dienes participated in this tandem reaction, and high regio-
selectivity was observed for the [4+3] cycloaddition in most
cases. Application of this method to the synthesis of natural
products and pharmaceutical agents is underway and will be
reported in due course.
[13] a) K. Miki, K. Ohe, S. Uemura, J. Org. Chem. 2003, 68, 8505;
b) B. W. Gung, L. N. Bailey, J. Wonser, Tetrahedron Lett. 2010,
51, 2251; c) D. Garayalde, K. Kruger, C. Nevado, Angew. Chem.
2011, 123, 941; Angew. Chem. Int. Ed. 2011, 50, 911.
[14] K. Saito, H. Sogou, T. Suga, H. Kusama, N. Iwasawa, J. Am.
Chem. Soc. 2011, 133, 689.
[15] P. A. Allegretti, E. M. Ferreira, Org. Lett. 2011, 13, 5924.
[16] For recent reviews on [4+3] cycloadditions, see: a) M. Harmata,
Adv. Synth. Catal. 2006, 348, 2297; b) M. Harmata, Chem.
Commun. 2010, 46, 8886; c) M. Harmata, Chem. Commun. 2010,
46, 8904; d) A. G. Lohse, R. P. Hsung, Chem. Eur. J. 2011, 17,
3812.
[17] For selected reviews on p-acidic metal catalysis, see: a) N.
Marion, S. P. Nolan, Angew. Chem. 2007, 119, 2806; Angew.
Chem. Int. Ed. 2007, 46, 2750; b) A. Fꢀrstner, P. W. Davies,
Angew. Chem. 2007, 119, 3478; Angew. Chem. Int. Ed. 2007, 46,
3410; c) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180; d) D. J.
Gorin, F. D. Toste, Nature 2007, 446, 395; e) S. Wang, G. Zhang,
L. Zhang, Synlett 2010, 692; f) A. S. K. Hashmi, Angew. Chem.
2010, 122, 5360; Angew. Chem. Int. Ed. 2010, 49, 5232; g) X.-Z.
Shu, D. Shu, C. M. Schienebeck, W. Tang, Chem. Soc. Rev. 2012,
41, 7698.
[18] a) D. Shu, X. Li, M. Zhang, P. J. Robichaux, W. Tang, Angew.
Chem. 2011, 123, 1382; Angew. Chem. Int. Ed. 2011, 50, 1346;
b) X. Li, S. Huang, C. M. Schienebeck, D. Shu, W. Tang, Org.
Lett. 2012, 14, 1584.
[19] S. Huang, X. Li, C. L. Lin, I. A. Guzei, W. Tang, Chem. Commun.
2012, 48, 2204.
[20] a) X.-z. Shu, S. Huang, D. Shu, I. A. Guzei, W. Tang, Angew.
Chem. 2011, 123, 8303; Angew. Chem. Int. Ed. 2011, 50, 8153;
b) X.-z. Shu, X. Li, D. Shu, S. Huang, C. M. Schienebeck, X.
Zhou, P. J. Robichaux, W. Tang, J. Am. Chem. Soc. 2012, 134,
5211.
Received: November 19, 2012
Published online: February 10, 2013
Keywords: cycloaddition · heterocycles ·
.
homogeneous catalysis · transition metals
[1] A. Shafiee, A. Ahond, A. M. Bui, Y. Langlois, C. Riche, P. Potier,
Tetrahedron Lett. 1976, 17, 921.
[2] M. Andriantsiferana, R. Besselievre, C. Riche, H. P. Husson,
Tetrahedron Lett. 1977, 18, 2587.
[3] a) A. R. Carroll, E. Hyde, J. Smith, R. J. Quinn, G. Guymer, P. I.
Forster, J. Org. Chem. 2005, 70, 1096; b) T. Taniguchi, C. L.
Martin, K. Monde, K. Nakanishi, N. Berova, L. E. Overman, J.
Nat. Prod. 2009, 72, 430.
[4] A. D. Napper, J. Hixon, T. McDonagh, K. Keavey, J. F. Pons, J.
Barker, W. T. Yau, P. Amouzegh, A. Flegg, E. Hamelin, R. J.
Thomas, M. Kates, S. Jones, M. A. Navia, J. Saunders, P. S.
DiStefano, R. Curtis, J. Med. Chem. 2005, 48, 8045.
[5] T. Barf, F. Lehmann, K. Hammer, S. Haile, E. Axen, C. Medina,
J. Uppenberg, S. Svensson, L. Rondahl, T. Lundbaeck, Bioorg.
Med. Chem. Lett. 2009, 19, 1745.
[6] E. Yamuna, R. A. Kumar, M. Zeller, K. J. R. Prasad, Eur. J. Med.
Chem. 2012, 47, 228.
[7] a) M. L. Bennasar, B. Vidal, J. Bosch, J. Am. Chem. Soc. 1993,
115, 5340; b) M. L. Bennasar, B. Vidal, J. Bosch, J. Org. Chem.
1997, 62, 3597; c) C. L. Martin, L. E. Overman, J. M. Rohde, J.
Am. Chem. Soc. 2008, 130, 7568; d) R. G. Vaswani, J. J. Day, J. L.
[21] C. J. Cramer, S. E. Barrows, J. Org. Chem. 1998, 63, 5523.
[22] Y. Ito, T. Hirao, T. Saegusa, J. Org. Chem. 1978, 43, 1011.
3240 www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 3237 –3240